lgG4-Related Disease is a multi-system disorder encompassing a host of previously described syndromes, all now recognized to be characterized by tumescent lesions, storiform fibrosis, obliterative phlebitis and large amounts of serum lgG4. Clinical improvement is seen with steroids in many subjects and B cell depletion is also clinically effective. Very little is known about the pathogenesis of this disorder or about the molecular and cellular basis for fibrosis in a host of apparently unrelated disorders. Studies will be performed to define T cell clonal expansions observed by Next Gen Sequencing approaches in subjects with this disease but with distinct organ involvements. Novel surface markers expressed only on effector T cell clones will be investigated as potential targets for therapy. Detailed interrogation of gene expression protein expression and metabolites will be performed by global as well as single cell RNAseq, multi color flow cytometry, by Cytof mass cytometry, and liquid chromatography-mass spectrometry on clonally expanded T cells and will be conducted in order to understand pathways of potential therapeutic significance that contribute to the development of these T cells as well as to their effector functions in this fibrotic inflammatory disease. A possible role for lgG4 antibodies in this disorder will also be examined. Next Gen Sequencing as well as single cell cloning and sequencing strategies will be used to define plasmablast expansions and to establish specific antibody heavy-light chain pairs that may contribute to the disease. Reagents will be thus generated to identify specific antigens using human ORFeome expression libraries as source of antigen. Determining the B cell specific protein antigen and the use of recombinant proteins will be used to assist the identification of T cell specific peptides. Studies will also be performed on genetic susceptibility to lgG4-RD using Fluidigm based MHC class II genotyping and if indicated from the Immunochip analyses by Exome sequencing. Global comparisons of gene and protein expression will inform the need for epigenetic profiling studies.